Arrhythmogenesis in Timothy Syndrome is associated with defects in Ca2+-dependent inactivation

Ivy E Dick,Wanjun Yang,David T Yue,Rosy Joshi-Mukherjee

doi:10.1038/ncomms10370

Ivy E Dick, Wanjun Yang + Show 2 more

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https://doi.org/10.1038/ncomms10370

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Abstract

Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias. The underlying defect is a single de novo missense mutation in CaV1.2 channels, either G406R or G402S. Notably, these mutations are often viewed as equivalent, as they produce comparable defects in voltage-dependent inactivation and cause similar manifestations in patients. Yet, their effects on calcium-dependent inactivation (CDI) have remained uncertain. Here, we find a significant defect in CDI in TS channels, and uncover a remarkable divergence in the underlying mechanism for G406R versus G402S variants. Moreover, expression of these TS channels in cultured adult guinea pig myocytes, combined with a quantitative ventricular myocyte model, reveals a threshold behaviour in the induction of arrhythmias due to TS channel expression, suggesting an important therapeutic principle: a small shift in the complement of mutant versus wild-type channels may confer significant clinical improvement.

Highlights

Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias
We could use whole-cell patch-clamp recordings to measure calcium-dependent inactivation (CDI) (Fig. 1b), which can be seen as the faster decay of the Ca2 þ current as compared with the Ba2 þ current and is quantified as the ratio of Ca2 þ current remaining after 300 ms (r300)[23]
Even in the context of strong voltage-dependent inactivation (VDI) seen in the presence of the b1b subunit, the effects on CDI are readily apparent in both splice backgrounds (Supplementary Figs 3 and 4) and can be detected in adult myocytes (Supplementary Fig. 5)

Summary

Introduction

Timothy Syndrome (TS) is a multisystem disorder, prominently featuring cardiac action potential prolongation with paroxysms of life-threatening arrhythmias. As a result of these differing expression profiles, TS type 2 patients lack syndactyly while displaying more severe cardiac deficits, with profoundly prolonged QT intervals[1,5] In both variants of TS, the mutations cause a disruption in the function of the CaV1.2 voltage-gated Ca2 þ channel. CaV1.2 channels employ two forms of feedback regulation—voltage-dependent inactivation (VDI) and Ca2 þ /calmodulin-dependent inactivation (CDI) Disruption of these regulatory mechanisms in various Ca2 þ channels is known to result in severe clinical phenotypes including autism, migraine, night blindness and ataxia[1,2,6,7,8], understanding the effects of the TS mutations on both these regulatory mechanisms may provide significant insight into the pathogenesis of TS. This result is verified in adult ventricular myocytes, establishing a threshold behaviour in the induction of arrhythmias due to TS mutations

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